| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1930604 | Biochemical and Biophysical Research Communications | 2011 | 6 Pages |
Interactions between the proteasome inhibitor, bortezomib, and the sphingosine kinase (SPK1) inhibitor, SKI, were examined in BCR/ABL human leukemia cells. Coexposure of K562 or chronic myeloid leukemia (CML) cells from patients to subtoxic concentrations of SKI (10 μM) and bortezomib (100 nM) resulted in a synergistic increase in caspase-3 cleavage and apoptosis. These events were associated with the downregulation of BCR–ABL and Mcl-1, and a marked reduction in SPK1 expression. In imatinib mesylate-resistant K562 cells that displayed decreased BCR–ABL expression, bortezomib/SKI treatment markedly increased apoptosis and inhibited colony-formation in association with the downregulation of Mcl-1. Finally, the bortezomib/SKI regimen also potently induced the downregulation of BCR/ABL and Mcl-1 in human leukemia cells. Collectively, these findings suggest that combining SKI and bortezomib may represent a novel strategy in leukemia, including apoptosis-resistant BCR–ABL+ hematologic malignancies.
Research highlights► Proteosome (bortezomib) and SPK1 inhibitors (SKI) are independent CML therapies. ► This novel study investigated their interaction in human BCR/ABL+ CML cells. ► Combination therapy activated caspase-3 and decreased anti-apoptotic factors. ► SKI sensitized BCR/ABL+ cells to bortezomib by downregulating Mcl-1. ► This combined treatment may be effective in CML patients with imatinib resistance.
